ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.838G>A (p.Glu280Lys) (rs62508698)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078532 SCV000110388 pathogenic not provided 2017-03-02 criteria provided, single submitter clinical testing
GeneDx RCV000078532 SCV000239076 pathogenic not provided 2018-11-29 criteria provided, single submitter clinical testing The E280K variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. The E280K variant has been associated with no residual phenylalanine hydroxylase enzyme activity (Pey et al., 2003; Pey et al., 2007). Patients who are homozygous for E280K or compound heterozygotes with a null PAH variant have been reported with moderate and classic phenylketonuria (PKU) (Pey et al., 2003).
Fulgent Genetics,Fulgent Genetics RCV000000610 SCV000611235 pathogenic Phenylketonuria 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000000610 SCV000629219 pathogenic Phenylketonuria 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 280 of the PAH protein (p.Glu280Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs62508698, ExAC 0.01%). This variant has been reported as homozygous or in combination with a different PAH variant in multiple individuals affected with phenylketonuria (PMID: 12655546, 17935162, 23500595, 2564729, 2014036). ClinVar contains an entry for this variant (Variation ID: 580). Experimental studies have shown that this missense abrogates PAH enzymatic activity (PMID: 12655546, 17935162, 21953985, 2014036). For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000000610 SCV000744094 pathogenic Phenylketonuria 2014-10-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078532 SCV000888355 pathogenic not provided 2016-04-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000000610 SCV000917919 pathogenic Phenylketonuria 2018-02-15 criteria provided, single submitter clinical testing Variant summary: PAH c.838G>A (p.Glu280Lys) results in a conservative amino acid change located in the C-terminal domain of the Aromatic amino acid hydroxylase (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The c.838G>A variant has been reported in the literature in several individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) either in a homozygous state or in a compound heterozygosity with other HPA variants considered as pathogenic (e.g. Pey 2003, Kayaalp 1997, Couce 2013, Aldamiz-Echevarria 2016). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, concluding that the variant affected both folding and catalysis (Pey 2003). The most pronounced variant effect results in <10% of normal activity. One study reported absent/minimal BH4 responsiveness for patients carrying the variant (Couce 2013). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Women's Health, Inc. RCV000000610 SCV001193931 pathogenic Phenylketonuria 2019-12-19 criteria provided, single submitter clinical testing NM_000277.1(PAH):c.838G>A(E280K) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 12655546, 11524738, 9781015, 17935162, 1971144, 23500595 and 2564729. Classification of NM_000277.1(PAH):c.838G>A(E280K) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
OMIM RCV000000610 SCV000020760 pathogenic Phenylketonuria 1997-01-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078532 SCV000119733 not provided not provided no assertion provided not provided
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000000610 SCV000746008 pathogenic Phenylketonuria 2016-11-09 no assertion criteria provided clinical testing

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